ABSTRACT Inherited retinal degenerative diseases such as retinitis pigmentosa and cone-rod dystrophies affect approximately one in 3,000 individuals worldwide. Age-related macular degeneration is the leading cause of blindness among the elderly. Despite a remarkable heterogeneity of disease-causing genes and pathogenesis, it is the progressive death of cone photoreceptors that ultimately leads to vision impairment and blindness. There is currently no treatment available for retinal degeneration. Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and apoptosis. In the retina, TH signaling plays a central role in cone opsin expression and patterning. Using several retinal degeneration mouse models, our preliminary studies showed that TH signaling affects cone viability. Suppressing TH signaling (by anti-thyroid treatment) preserves cones and stimulating TH signaling (by thyroid hormone T3 treatment) deteriorates cones. TH signaling in local tissue is primarily regulated via TH receptor (ThR) and the enzyme that inactivates T3, type 3 iodothyronine deiodinase (DIO3). The objective of this study is to determine if suppressing TH signaling locally in the retina preserves cones. We propose two specific aims to address the question. The first aim is to determine whether blocking ThR in the retina preserves cones in retinal degeneration model mice. Rpe65-/-, a model of Leber congenital amaurosis, and cpfl1, a model of achromatopsia, mice will be treated with ThR antagonists via ocular delivery, and cone survival will be evaluated following drug administration. Cone survival will also be evaluated in Rpe65-/- and cpfl1 mice lacking ThR (cones express type of ThR, Rpe65-/-/Thr-/- and cpfl1/Thr-/-) to determine whether cones are preserved when ThR is absent. The second aim is to determine whether enhancing expression/function of DIO3 in the retina preserves cones. We will overexpress DIO3 in the retinas of Rpe65-/- and cpfl1 mice through adeno-associated viral (AAV) mediated transgene delivery. Cone survival will be evaluated following transgene delivery. Completion of the proposed study will determine whether suppressing TH signaling locally in the retina preserves cones in retinal degeneration. Specifically, it will establish whether blocking ThR and overexpressing/activating DIO3 in the retina protects cones. We anticipate an outcome that will lead to a novel and substantially different approach for retinal degeneration management.